Sexual differences in onset of disease and response to exercise in a transgenic model of ALS

Veldink, Jan H.; Bär, P.R.; Joosten, Elbert A.J.; Otten, Marielle A.; Wokke, John H. J.; Berg, Leonard H. van den

doi:10.1016/s0960-8966(03)00104-4

Cited by 207 publications

(160 citation statements)

References 29 publications

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“…For example, studies with untreated mutant SOD1 mice [31] and rats [52], including results from the present study, demonstrate that disease onset and overall survival occur earlier on average in males. In response to an exercise regimen therapy, delayed disease onset and survival was noted in only female mice [55], while AAV2 IGF-1 promoted benefit selectively in males in the present study. While the mechanism for the male-only effect seen in the present study is unknown, potential reasons include differences in disease progression, mutant SOD1 expression, sex hormones and/or levels and sensitivity of components of the IGF-1 system.…”

Section: Sex-specific Effectssupporting

confidence: 41%

“…Sex-specific differences in disease onset and progression [31,40,52,55] and response to therapeutic interventions [16] have been noted in CNS disorders, including ALS. For example, studies with untreated mutant SOD1 mice [31] and rats [52], including results from the present study, demonstrate that disease onset and overall survival occur earlier on average in males.…”

Section: Sex-specific Effectsmentioning

confidence: 99%

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Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS

Lepore

Haenggeli

Gasmi³

et al. 2007

Brain Research

113

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The potent neuroprotective activities of neurotrophic factors, including insulin-like growth factor 1 (IGF-1), make them promising candidates for treatment of amyotrophic lateral sclerosis (ALS). In an effort to maximize rate of motor neuron transduction, achieve high levels of spinal IGF-1, and thus enhance therapeutic benefit, we injected an adeno-associated virus 2 (AAV2)-based vector encoding human IGF-1 (CERE-130) into lumbar spinal cord parenchyma of SOD1 G93A mice. We observed robust and long-term intraspinal IGF-1 expression and partial rescue of lumbar spinal cord motor neurons, as well as sex-specific delayed disease onset, weight loss, decline in hindlimb grip strength and increased animal survival.

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Section: Sex-specific Effectssupporting

confidence: 41%

Section: Sex-specific Effectsmentioning

confidence: 99%

Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS

Lepore

Haenggeli

Gasmi³

et al. 2007

Brain Research

113

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“…Sex‐specific differences in disease onset and progression as well as response to therapy have been reported in a number of studies 17, 25, 34. In the current study, we found no significant difference when we compared overall disease onset and survival between male and female α CAR IGF‐1 LV‐treated mice.…”

Section: Discussionsupporting

confidence: 46%

αCAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice

Eleftheriadou

Manolaras

Irvine

et al. 2016

Ann Clin Transl Neurol

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ObjectiveWe have previously described the generation of coxsackievirus and adenovirus receptor (α CAR)‐targeted vector, and shown that intramuscular delivery in mouse leg muscles resulted in specific retrograde transduction of lumbar‐motor neurons (MNs). Here, we utilized the α CAR‐targeted vector to investigate the in vivo neuroprotective effects of lentivirally expressed IGF‐1 for inducing neuronal survival and ameliorating the neuropathology and behavioral phenotypes of the SOD1G93A mouse model of ALS.MethodsWe produced cell factories of IGF‐1 expressing lentiviral vectors (LVs) bearing α CAR or Vesicular Stomatitis Virus glycoprotein (VSV‐G) on their surface so as to compare neuroprotection from MN transduced versus muscle transduced cells. We performed intramuscular delivery of either α CAR IGF‐1 or VSVG IGF‐1 LVs into key muscles of SOD1G93A mice prior to disease onset at day 28. Motor performance, coordination and gait analysis were assessed weekly.ResultsWe observed substantial therapeutic efficacy only with the α CAR IGF‐1 LV pretreatment with up to 50% extension of survival compared to controls. α CAR IGF‐1 LV‐treated animals retained muscle tone and had better motor performance during their prolonged survival. Histological analysis of spinal cord samples at end‐stage further confirmed that α CAR IGF‐1 LV treatment delays disease onset by increasing MN survival compared with age‐matched controls. Intrastriatal injection of α CAR eGFP LV in rats leads to transduction of neurons and glia locally and neurons in olfactory bulb distally.InterpretationOur data are indicative of the efficacy of the α CAR IGF‐1 LV in this model and support its candidacy for early noninvasive neuroprotective therapy in ALS.

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“…As mentioned above, there are 2 transgenic lines of SOD1-G93A mice that differ in disease onset and progression. Within-line sex-based differences in disease onset and progression have been identified in at least two studies (Miana-Mena et al, 2005;Veldink et al, 2003). Additionally, another SOD1 mutant model carrying the G86R mutation is available for study.…”

Section: Resultsmentioning

confidence: 99%

Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice

2008

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Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease affecting upper and lower motor neurons. Symptom onset may occur in the muscles of the limbs (spinal onset) or those of the head and neck (bulbar onset). Bulbar involvement is particularly important in ALS as it is associated with increased morbidity and mortality. The purpose of this study was to characterize bulbar motor deficits in the SOD1-G93A mouse model of familial ALS. We measured orolingual motor function by placing thirsty mice in a customized operant chamber that allows for measurement of tongue force and lick rhythm as animals lick water from an isometric disc. Testing spanned the pre-symptomatic, symptomatic, and end-stage segments of the disease. Rotarod performance, fore-and hindlimb grip strength, and locomotor activity were also monitored regularly during this period. We found that spinal involvement was apparent first, with both fore-and hindlimb grip strength being affected in SOD1-G93A mice from the onset of testing (64 days of age). Rotarod performance was affected by 71 days of age. Locomotor activity was not affected, even near end-stage. Bulbar involvement appeared much later, with tongue motility being affected by 100 days of age. Tongue force was affected by 115 days of age. To our knowledge, these findings are the first to describe the onset of bulbar v. spinal motor signs and characterize orolingual motor deficits in this preclinical model of ALS.

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Sexual differences in onset of disease and response to exercise in a transgenic model of ALS

Cited by 207 publications

References 29 publications

Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS

Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS

αCAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice

Time-course and characterization of orolingual motor deficits in B6SJL-Tg(SOD1-G93A)1Gur/J mice

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